Proteolytically released Lasso/teneurin-2 induces axonal attraction by interacting with latrophilin-1 on axonal growth cones

The brain is a complex mesh of interconnected neurons, with each cell making tens, hundreds, or even thousands of connections. These links can stretch over long distances, and establishing them correctly during development is essential. Developing neurons send out long and thin structures, called axons, to reach distant cells. To guide these growing axons, neurons release molecules that work as traffic signals: some attract axons whilst others repel them, helping the burgeoning structures to twist and turn along their travel paths. When an axon reaches its target cell, the two cells join to each other by forming a structure called a synapse. To make the connection, surface proteins on the axon latch onto matching proteins on the target cell, zipping up the synapse. There are many different types of synapses in the brain, but we only know a few of the surface molecules involved in their creation – not enough to explain synaptic variety. Two of these surface proteins are latrophilin-1, which is produced by the growing axon, and Lasso, which sits on the membrane of the target cell. The two proteins interact strongly, anchoring the axon to the target cell and allowing the synapse to form. However, a previous recent discovery by Vysokov et al. has revealed that an enzyme can also cut Lasso from the membrane of the target cell. The ‘free’ protein can still interact with latrophilin-1, but as it is shed by the target cell, it can no longer serve as an anchor for the synapse. Could it be that free Lasso acts as a traffic signal instead? Here, Vysokov et al. tried to answer this by growing neurons from a part of the brain called the hippocampus in a special labyrinth dish. When free Lasso was gradually introduced in the culture through microscopic channels, it interacted with latrophilin-1 on the surface of the axons. This triggered internal changes that led the axons to add more membrane where they had sensed Lasso, making them grow towards the source of the signal. The results demonstrate that a target cell can both carry and release Lasso, using this duplicitous protein to help attract growing axons as well as anchor them. The work by Vysokov et al. contributes to our knowledge of how neurons normally connect, which could shed light on how this process can go wrong. This may be relevant to understand conditions such as schizophrenia and ADHD, where patients’ brains often show incorrect wiring.